Persistent viruses, such as human immunodeficiency virus (HIV), cause major health problems worldwide and are extraordinarily difficult to clear following the establishment of persistence. Given the challenges associated with clearing persistent infections, it is important to develop and mechanistically understand therapeutic strategies that successfully achieve viral eradication without inducing permanent damage to the host. We model states of persistent infection in our laboratory using lymphocytic choriomeningitis virus (LCMV), a mouse as well as human pathogen. Persistent LCMV infections can be established by infecting mice in utero or by infecting adult mice intravenously with specific strains of the virus. When mice are persistently infected at birth or in utero with LCMV, the virus establishes systemic persistence, infecting both peripheral tissues as well as the central nervous system (CNS). Adult LCMV carrier mice are centrally tolerant to the virus at the T cell level and thus unable to eradicate the pathogen. We model persistent infection in adult mice by infecting with more aggressive strains of LCMV such as clone 13. Infection with clone 13 initiates a state of persistence that shares some important features with HIV-1 infection in humans, including infection / impairment of dendritic cells, exhaustion / deletion of the virus-specific T cells, and rapid establishment of viral persistence in the CNS as well as peripheral tissues. Both of the aforementioned models of LCMV persistence enable us to study how the immune system can be manipulated or supplemented to control a persistent viral infection in the CNS and periphery. One area of active research in the laboratory is on the development of humoral responses to persistent viral infections. In addition to T lymphocytes, B cells play an important role in the control of persistent viral infections through production of antiviral antibodies. In particular, neutralizing antibodies are especially beneficial because they impede the ability of viruses to spread and infect new host cells. However, neutralizing antibodies do not always emerge during states of persistent infection, and the mechanisms underlying this immunological failure are not completely understood. Using LCMV as a model, we have recently examined how a persistent viral infection can suppress neutralizing humoral immunity. By tracking the fate of virus-specific B cells in vivo, we discovered that LCMV-specific B cells were rapidly deleted within a few days of persistent infection, and this deletion was completely reversed by blockade of type I interferon (IFN-I) signaling. Early interference with IFN-I signaling promoted survival and differentiation of LCMV-specific B cells, which accelerated the generation of neutralizing antibodies. This marked improvement in antiviral humoral immunity did not rely on the cessation of IFN-I signaling in B cells but on alterations in the virus-specific CD8+ T cell response. We observed that cytotoxic T lymphocytes (CTLs) productively engaged and killed antiviral B cells within the first few days of infection. Blockade of IFN-I signaling protected LCMV-specific B cells by promoting CTL dysfunction. Importantly, therapeutic manipulation of this pathway may facilitate efforts to promote humoral immunity during persistent viral infection in humans. We recently sought insights into this process by studying Within the CNS, we are also focused on the immunotherapeutic clearance of persistently infected parenchymal cell populations like microglia and neurons. Microglia have become a centerpiece in our laboratory over the past few years given their plastic nature, interesting dynamic properties, and ability to orchestrate both sterile and antiviral immune responses. Following administration of adoptive immunotherapy in mice persistently infected from birth with LCMV, we observed that antiviral T cells recruited into the CNS promote the conversion of nearly all microglia into CD11c+ antigen presenting cells (APCs). CD11c is a marker commonly used to identify dendritic cells (DCs), and we have previously shown that interactions with host DCs are required for successful viral clearance following adoptive immunotherapy. Interestingly, microglia can also acquire DC-like properties following adoptive immunotherapy. They upregulate antigen-presenting machinery and release chemoattractants that recruit antiviral T cells. In fact, we showed using TPM that therapeutic antiviral CD8+ and CD4+ T cells directly engage CD11c+ microglia during adoptive immunotherapy. Even more impressive was the fact that these interactions resulted in viral clearance from microglia without evidence of cytopathology. We obtained data showing that microglia are resistant to apoptosis and are purged of virus in a noncytopathic manner. We postulate that microglia have acquired a mechanism to dampen the cytopathic effector mechanisms of T cells in order to help preserve brain tissue during viral clearance. We are in the process of attempting to identify these regulatory pathways.